New class of therapeutics that enhance small molecule diffusion

ABSTRACT

The subject application relates to novel compositions containing a diffusion enhancing compound and their use in treating a variety of disorders.

This application is a divisional of U.S. patent application Ser. No.12/289,713, filed Oct. 31, 2008, which claims priority from U.S.Provisional Patent Application No. 61/001,095, filed on Oct. 31, 2007,the entire contents of which are hereby incorporated by reference.

The subject application relates to novel compositions and their use inenhancing small molecule diffusion, and in the case of oxygen in vivo,oxygenation of tissues. This class of compounds is called diffusionenhancing compounds.

BACKGROUND OF THE INVENTION

The terms ‘kosmotrope’ (order-maker) and ‘chaotrope’ (disorder-maker)originally denoted solutes that stabilized, or destabilizedrespectively, proteins and membranes. More recently, the terms have alsobeen used to refer to compounds having the apparently correlatingproperty of increasing, or decreasing respectively, the structuring(ordering) of water. Some compounds (e.g. urea) can act as kosmotropesand chaotropes, depending on the concentration of the compound in ahydrogen bonding environment such as water.

Both the extent and strength of hydrogen bonding may be changed by akosmotrope. The effect of a kosmotrope on increasing the amount ofhydrogen bonding in an aqueous solution is especially important. Byeffecting such a change in the hydrogen bonding in the solution, akosmotrope shifts the local equilibrium shown below to the left (andchaotropes shift it to the right)

-   -   less dense water        more dense water.        In other words, the addition of a kosmotrope to an aqueous        system results in a decrease in density of that system. So, by        increasing the structure, or order, of the water through the        formation of more hydrogen bonds, kosmotropes cause the solution        density to decrease.

Kosmotropes are currently used to stabilize proteins, such as enzymes.It is also said that they affect the phase behavior of lipids. Somewell-known kosmotropes are proline, glycine betaine and trehalose. Seealso Moelbert, S. et al., Biophysical Chemistry, 112, 45-57, 2004. Thewebsite: http://www.lsbu.ac.uk is a good reference for kosmotropes andchaotropes.

Gainer et al. Chem. Eng. Commun. 15: 323-329, 1982, showed that crocetincaused an increase in the specific volume of water.

Gainer et al. Ind. Engr. Chem. Research, 33: 2341-2344, 1994 showed thatthe diffusivity through a solution was proportional to the change in thespecific volume.

Carotenoids are a class of hydrocarbons consisting of isoprenoid units.The backbone of the molecule consists of conjugated carbon-carbon doubleand single bonds, and can also have pendant groups. Carotenoids such ascrocetin and trans sodium crocetinate (TSC) are known to increase thediffusivity of oxygen in water.

U.S. Pat. No. 6,060,511 relates to trans sodium crocetinate (TSC) andits uses. The patent covers various uses of TSC such as improving oxygendiffusivity and treatment of hemorrhagic shock.

U.S. patent application Ser. No. 10/647,132 relates to synthesis methodsfor making bipolar trans carotenoid salts (BTC) and methods of usingthem.

U.S. patent application Ser. No. 11/361,054 relates to improved BTCsynthesis methods and novel uses of the BTC.

U.S. Patent application Ser. No. 60/907,718 relates to the use ofbipolar trans carotenoids as a pretreatment and in the treatment ofperipheral vascular disease.

Trans sodium crocetinate (TSC) increases the amount of hydrogen bondingwhen dissolved in water, Stennett et al. J. Phys. Chem. B, 110:18078-18080, 2006.

In Okonkwo et al., Neurosci Lett. 352(2):97-100, 2003, the authorsmeasured brain oxygen levels in rats. As expected, having the ratsbreathe 100% oxygen caused the brain oxygen level to increase. Anunexpected result was that administering TSC to rats breathing 100%oxygen further increased the brain oxygen level. The combination of 100%oxygen and TSC gave a greater effect than either one alone. In animalssuffering from an oxygen deficiency, TSC can be used as a treatment,Giassi, L. J. et al. J. Trauma, 51: 932-938, 2001, and Gainer et al.Pulm. Pharmacol. & Therapeutics, 18: 213-216 (2005).

SUMMARY OF THE INVENTION

The subject invention relates to pharmaceutical compositions comprisinga diffusion enhancing compound such as a kosmotrope, and apharmaceutically acceptable carrier.

The invention also relates to a variety of methods of treatmentincluding methods of enhancing the diffusion of oxygen, treatinghemorrhagic shock, or treating a hypoxic condition in a mammalcomprising administering to said mammal a therapeutically effectiveamount of a diffusion enhancing compound other than a bipolar transcarotenoid.

The invention also relates to a method of treating cancer comprisingadministering to said mammal a therapeutically effective amount of adiffusion enhancing compound as an adjunct to radiation therapy and/orchemotherapy.

The invention also relates to treating diseases where organs do not getenough oxygen such as Wegener's granulomatosis with a diffusionenhancing compound including bipolar trans carotenoids, and to treatingarthritis with a diffusion enhancing compound including a bipolar transcarotenoid other than crocetin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph that shows the percentage increases in thediffusivities of glucose due to each kosmotrope.

FIGS. 2, 3, and 4 are graphs that show that trehalose, TSC, or glycinebetaine result in an increased oxygen transport across the skin.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention relates to novel compositions and their use intreating a variety of disorders where enhanced tissue oxygenation isbeneficial. As used herein, “diffusion enhancing compound” is a compoundthat causes an increase in the rate of movement of a small moleculethrough an aqueous system. Diffusion enhancing compounds increase thespecific volume of the aqueous system by increasing water structure byaffecting the extent and strength of hydrogen bonding among watermolecules.

The movement of oxygen through plasma is thought to be a limiting, orcontrolling, step in the uptake and release of oxygen from red bloodcells (Holland, RAB, Shibata, H., Scheid, P, Piiper, J: RespirationPhysiology, 59: 71-91, 1988; Huxley, VH, Kutchai, H: J. Physiology, 316:75-83, 1981; Yamaguchi, K, Nguyen-Phu, P. Scheid, P, Piiper, J: J.Applied Physiology, 58: 1215-1224, 1985). Thus, in order to increase therate at which oxygen gets to the body tissues, it is important toenhance its movement through the plasma.

Oxygen can move through the plasma, especially in the smaller bloodvessels (the capillaries), via molecular diffusion which depends on theoxygen concentration gradient as well as a factor called the diffusioncoefficient (or diffusivity). This diffusion coefficient reflects thebasic resistance of the plasma to the movement of other molecules likeoxygen, through it. If it were possible to decrease the resistance ofthe plasma, oxygen would move faster through it and this would bereflected as an increased diffusivity. One way to do this is to decreasethe plasma density with a diffusion enhancing compound.

Usually when one adds a chemical compound to a given volume of plasma,the density (mass/volume) increases. Thus, in order to decrease thedensity of plasma when adding another substance, the compound added mustalso increase the volume of the liquid as well as the mass of thesolution. This will result in a decrease in the density (mass/volume).Specific volume is inversely related to the density. Increasing thespecific volume (volume/mass) of the blood plasma implies altering the“structure” of its water molecules.

Compounds that decrease the water density and increase the specificvolume are kosmotropes. Kosmotropes are said to shift the equilibriumshown below to the left while compounds called chaotropes shift it tothe right:

-   -   less dense water⇄more dense water

Thus, kosmotropes are diffusion enhancing compounds. How they act todecrease water density has been suggested to be through increasing thewater structure through increased hydrogen bonding. Plasma is mostlywater and water molecules are bound to each other by hydrogen bonds.

The terms ‘kosmotrope’ (order-maker) and ‘chaotrope’ (disorder-maker)also denote solutes that stabilized, or destabilized respectively,proteins and membranes. Another term used to classify compounds and ionswhich stabilize proteins in cells is osmolyte. A number of chemicalcompounds are included on both the lists of osmolytes and the lists ofkosmotropes. Osmolytes are frequently concentrated inside tissue cells.

As used herein “diffusion enhancing kosmotrope” denotes kosmotropeshaving the capability to increase the structuring (ordering) of water,resulting in a decreased density and an increased diffusivity of oxygenthrough an aqueous solution like plasma.

Both the extent and strength of hydrogen bonding can be changed by akosmotrope. Some compounds (e.g. urea) can act as both a kosmotrope anda chaotrope, depending on the concentration of the compound in ahydrogen bonding environment such as water. Some of the better-knownkosmotropes are proline, glycine betaine and trehalose.

As shown in the Examples below, it can be seen that kosmotropes increasethe diffusivity of solutes (such as glucose and oxygen) through aqueoussolutions. They do this because kosmotropes cause increased hydrogenbonding among the water molecules, which, in turn, leads to a less denseliquid structure.

Also included in diffusion enhancing compounds are the bipolar transcarotenoid compounds. Carotenoids are not found on standard lists ofkosmotropes; however, it has been found that a carotenoid, trans sodiumcrocetinate (TSC), can enhance water structure (Laidig, K. E., Gainer,J. L., Daggett, Valerie: Journal of the American Chemical Society, 120:9394-9395, 1998) as well as cause increased hydrogen-bonding in water(Stennett, A. K., Dempsey, G. L., Gainer, J. L.: J. of Physical Chem. B,110: 18078-18080, 2006). Trans sodium crocetinate is also known toincrease the diffusivity of both oxygen and glucose (Stennett, A. K.,Dempsey, G. L., Gainer, J. L.: J. of Physical Chem. B, 110: 18078-18080,2006).

Thus, diffusion enhancing compounds can cause increased water structureand decreased density, resulting in increased diffusivity throughaqueous solutions such as blood plasma. These properties enable thesecompounds to perform as therapeutics to increase tissue oxygenation.

Other diffusion enhancing compounds increase the diffusion throughaqueous solutions through the same mechanism, i.e., by decreasing thedensity and altering the water structure by increasing the hydrogenbonding among the water molecules. There are accepted methods ofdetermining whether or not a compound increases the hydrogen bonding ofwater (Stennett et al., J. Phys. Chem. B., 110, 18078-18080, 2006).

Diffusion enhancing compounds will increase tissue oxygenation in amammal. If the mammal is oxygen-deficient, or hypoxic, then no enrichedoxygen gases are needed to observe the effect of a diffusion enhancingcompound. If the mammal is not suffering from a form of hypoxia, thenenriched oxygen gases plus a diffusion enhancing compound will delivermore oxygen to the tissue than the enriched oxygen gases can do alone.

Compounds and Compositions of the Invention

Included in the Compounds of the Invention are the following diffusionenhancing compounds:

Bipolar Trans Carotenoids such as trans sodium crocetinate (TSC). Seealso the compounds disclosed in U.S. Ser. No. 10/647,132 and U.S. Ser.No. 11/361,054 hereby incorporated by reference in their entirety

Kosmotropes are effective in enhancing diffusion. As used herein, theterm “kosmotrope” means a chemical compound that results in increasedwater structure by increasing hydrogen bonding among water molecules.Another characteristic of the kosmotropes of the invention are non toxicat therapeutically effective concentrations. Kosmotropes of theinvention include:

Trimethylamine N-oxide Proline Ectoine

Trehalose, maltose and other disaccharides that can increase hydrogenbondingGlycine betaine

3-Dimethylsulfoniopropionate

Urea at certain concentrations [it can be the opposite (a chaotrope) atother concentrations]

Maltose Glycerol

Small or multiply-charged ions, with high charge density (e.g. SO₄ ²⁻,HPO₄ ²⁻, Mg²⁺, Ca²⁺, Li⁺, Na⁺, OH⁻, F⁻, Cl⁻)

t-butanol

Fructose

DMSO (dimethylsulfoxide) at certain concentrations (it is like urea inthat it is a chaotrope at other concentrations)and other related compounds which also function as kosmotropes.

Other compounds that enhance the diffusion of oxygen in an aqueoussystem are also useful. In addition to the compounds above, the skilledperson can use assays as described herein and known to those skilled inthe art, to identify diffusion enhancing compounds that increase thespecific volume of an aqueous system by increasing water structure byaffecting the extent and strength of hydrogen bonding among watermolecules.

The compounds of the subject invention are all manufactured to bepharmaceutical grade. Although the compounds of the invention can beadministered alone, they can also be administered as part of apharmaceutical composition. Such formulations can includepharmaceutically acceptable carriers known to those skilled in the artas well as other therapeutic agents-see below. Advantageously, theformulation does not include a compound that inhibits the ability of thecompounds of the invention to improve diffusivity.

The compounds can be formulated using agents known to increasesolubility such as cyclodextrins, polyethylene glycol, glycols, etc.Other agents can be added to buffer the diffusion enhancing compounds.Other agents can be added to affect the osmolality, as well ascompounding agents needed for oral formulations.

The formulations can conveniently be presented in unit dosage form,e.g., tablets and sustained release capsules, and can be prepared andadministered by methods known in the art of pharmacy. The formulationcan be for immediate, or slow or controlled release of the diffusionenhancing compound. See, for example, the controlled release formulationof WO 99/15150 hereby incorporated by reference in its entirety.

Formulations of the present invention suitable for oral administrationcan be presented as discrete units such as pills, capsules, cachets ortablets, as powder or granules, or as a solution, suspension oremulsion. Formulations suitable for oral administration further includelozenges, pastilles, and inhalation mists administered in a suitablebase or liquid carrier. Formulations for topical administration to theskin can be presented as ointments, creams, gels, and pastes comprisingthe active agent and a pharmaceutically acceptable carrier or in atransdermal patch.

Formulations suitable for nasal administration wherein the carrier is asolid include powders of a particular size that can be administered byrapid inhalation through the nasal passage. Suitable formulationswherein the carrier is a liquid can be administered, for example as anasal spray or drops.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions that can contain antioxidants,buffers, bacteriostats, compounds to improve solubility of the activeagent, solutes which render the formulation isotonic with the blood ofthe intended recipient, and aqueous and nonaqueous sterile suspensionswhich can include suspending agents and thickening agents.

The formulations can be presented in unit or multi-dose containers, forexample sealed ampules and vials, and can be lyophilized orcrystallized, requiring only the addition of the sterile liquid carriersuch as water for injection immediately prior to use. Injectionsolutions and suspensions can be prepared from sterile powders, granulesand tablets.

Therapeutic Uses and Modes of Administration of the Compounds andCompositions of the Invention

The compounds and compositions of the invention have therapeutic uses intreating mammals having conditions of reduced oxygen usage.

The uses include those disclosed in commonly owned U.S. Pat. No.6,060,511, U.S. patent application Ser. No. 10/647,132, U.S. patentapplication Ser. No. 11/361,054, and U.S. Patent application Ser. No.60/907,718 each of which is hereby incorporated by reference in itsentirety. The compounds are useful in the treatment of:

hemorrhagic shock, respiratory disease, asthma, emphysema, ALI, ARDS,COPD

cardiovascular disease, atherosclerosis, myocardial infarction,hypertension, ischemia, stroke, traumatic brain injury,

Alzheimer's disease,

arthritis,

anemia, (anemia of prematurity, Fanconi anemia, hymolytic anemia,microcytic anemia, a normochromic anemia, a macrocytic anemia,hereditary spherocytosis, sickle-cell anemia, warm autoimmune hemolyticanemia, cold agglutinin hemolytic anemia),

chronic renal failure, hypertension, cerebral edema, papillomas, spinalchord injuries

cancer (advantageously as an adjunct to i) radiation therapy includingexternal beam radiation, gamma knife, brachytherapy, tomotherapy, andproton beam, including fractionated, 3D conformal radiotherapy,intracavitary radiation, and intensity modulated radiotherapy (IMRT),and/or ii) chemotherapy including temozolimide),

diabetes, diabetic retinopathy,

peripheral vascular disease/claudication, embolism, blood clot, spinalstenosis/neurogenic claudication,

diseases where organs do not get enough oxygen such as Wegener'sgranulomatosis

performance when respiration/exertion is increased/stressed,

The compounds and compositions of the invention are also useful as apretreatment or for treating mammals at risk for the above-noteddiseases/conditions.

As evidenced by the Examples below, diffusion enhancing compoundsincrease tissue oxygenation and thus can be used to treat oxygendeficient diseases. The concentration/dose of the diffusion enhancingcompound selected will be that concentration that causes increasedhydrogen bonding among the water molecules of the blood plasma andresults in increased diffusivity. This concentration can be determinedby those skilled in the art.

Typically the diffusion enhancing compounds are administered by anysuitable route including oral, nasal or inhalation, topical, parenteral(including subcutaneous, intramuscular, intravenous, intradermal,transdermal and intraosseus), vaginal or rectal. The preferred route ofadministration will depend on the circumstances. An inhalation route isadvantageous for treatment in emergency situations, where it isnecessary for the diffusion enhancing compound to enter the bloodstreamvery quickly. The formulations thus include those suitable foradministration through such routes (liquid or powder to be nebulized).It will be appreciated that the preferred route may vary, for example,with the condition and age of the patient.

Appropriate dosages of the compounds and compositions of the inventionas well as the mode of administration, will depend on the metabolism ofthe given compound, and the severity of the condition being treated. Fora dose to be “therapeutically effective”, it must have the desiredeffect, i.e. increase diffusivity. The minimum dosage needed fortreatment for any of these diffusion enhancing compounds is that atwhich the diffusivity increases. The therapeutically effective dosage ofthe compounds of the invention will depend upon the condition treated,the severity of the condition, the stage and individual characteristicsof each mammalian patient addressed, and the clearance of the diffusionenhancing effect.

In one embodiment, more than one diffusion enhancing compound isadministered. In another embodiment, the diffusion enhancing compound isadministered along with oxygen. Alternatively, hemoglobins orfluorocarbons and a diffusion enhancing compound can be given together.In a still further embodiment, the diffusion enhancing compound isadministered along with an erythropoiesis stimulating compound such aserythropoietin.

In another embodiment, diffusion enhancing compound can be used toincrease the diffusivity of other physiologically important moleculesother than oxygen such as glucose, CO2, or NO.

Non-Therapeutic Uses

Lastly, the compounds of the invention can be used to enhancediffusivity in aqueous systems outside the body, for example infermentations and other cultures of microorganisms.

The following examples are illustrative, but not limiting of thecompounds, compositions and methods of the present invention. Othersuitable modifications, and adaptations of a variety of conditions andparameters normally encountered which are obvious to those skilled inthe art are within the spirit and scope of the invention.

EXAMPLES Example 1 Increasing Glucose and Oxygen Transport In Vitro

The effect of each of 3 kosmotropes (proline, betaine and trehalose) onthe rate of diffusion though a water solution has been tested in thefollowing manner.

Glucose Diffusion

The diffusion of glucose through aqueous solutions of theabove-mentioned kosmotropes was measured using a microinterferometricmethod, Secor, R. M., AIChE Journal, 11: 452-456, 1965.

In this method, a wedge is formed by two microscope slides that have apartial coating of a metal such as aluminum on the inner sides of thewedge. The wedge is placed on a microscope stage and illuminated frombelow using some source of monochromatic light, such as a helium-neonlaser. As the light passes through the wedge, the partial coating ofaluminum allows some light to be transmitted, while some is reflected.This creates constructive and destructive lines known as interferencefringes. The interference fringes can then be magnified by a microscopeand recorded with a camera.

Molecules of glucose will diffuse along a concentration gradient ofglucose. Since the refractive index of the solution is related to theconcentration of the glucose, the fringes at a given point will changewith time. From the time behavior in the fringe pattern, one cancalculate the diffusion coefficient, or diffusivity, at each timeincrement. These values become constant at longer times, and that finalvalue is taken to be the diffusion coefficient of glucose in thatparticular aqueous solution.

Solutions of three kosmotropes (proline, betaine and trehalose) in waterwere made, so that the solutions contained about 10 μM of each of thekosmotropes. Using the trehalose solution as an example, the diffusivityof glucose through each of these solutions was then measured in thefollowing way.

The trehalose solution was divided into two parts. A strip of one partof the trehalose solution was placed on one of the coated slides. Awedge was formed by placing a cover slip on one end of one of the coatedslides and then resting the other coated slide on top. The wedge wasplaced on a microscope stage and a light source was turned on. A camerarecorded the resulting fringe pattern.

Glucose was added to the second portion of the trehalose solution sothat the glucose concentration in that solution was 0.9 molar. A drop ofthis trehalose-glucose solution was then introduced into the wedge,using a syringe, in such a manner so that the drop touched the strip oftrehalose solution that was already in the wedge. Care was taken toassure that the two solutions did not mix when they touched, and, ifthey did, the solution was discarded and the procedure started over.

A stopwatch was turned on at the time that the two solutions touched.Pictures of the fringe patterns were taken at various times over thenext several minutes. Using these pictures, it is possible to calculatethe diffusivity of glucose through the trehalose solution. Thatcalculation method is given in Secor, R. M., AIChE Journal, 11: 452-456,1965.

The measurements were done at a temperature of 25° C., and the apparatuswas calibrated by measuring the diffusivity of glucose in plaindistilled water, with the value obtained being (6.9+0.3)×10⁻⁶ cm²/s.This closely corresponds to the CRC Handbook value of 6.7×10⁻⁶ cm²/s CRCHandbook of Chemistry and Physics, edited by D. R. Lide, CRC Press, BocaRaton, Fla., 1998, p. 6-181.

The values of the diffusivity of glucose through the solutionscontaining the trehalose and the other kosmotropes were greater than thevalue of glucose through plain water. The percentage increases in thediffusivities of glucose due to each kosmotrope is shown in FIG. 1.

The preceding diffusion measurement was also done for TSC in water, andit was found that TSC caused an increase in the diffusivity of glucosethrough water at TSC concentrations from 1 μmole/liter to around 200μmole/liter of around 30%, Stennett, A. et al. J. Phys. Chem. B, 110:18078-18080, 2006.

Oxygen Diffusion

In addition, the diffusivity of oxygen through TSC-water solutions wasalso measured over the same TSC concentration range as for the glucosediffusion studies. Since oxygen is a gas, the diffusivity had to bemeasured differently, in an apparatus commonly used for such purposes,Goldstick, T. K., PhD Dissertation, University of California, Berkeley,Calif., 1966, pps. 13-28. In that experiment, the movement of oxygenacross a liquid layer is determined by measuring the concentration atthe opposite boundary of the liquid layer over time using an electrode,and the diffusivity calculated. All measurements were done at 25° C.,and it was found that TSC increases the diffusion of both oxygen andglucose through water by a similar percentage, Stennett, A. K. et al. J.Phys. Chem. B, 110: 18078-18080, 2006.

Based on these data, it can be seen that kosmotropes increase thediffusivity of solutes (such as glucose and oxygen) through aqueoussolutions.

Example 2 Increasing Oxygen Transport In Vivo

Diffusion enhancing compounds such as kosmotropes increase the oxygentransport in vivo. In the subject experiment, the oxygen diffusingthrough the skin of a normal, non-diseased rat was measured using atranscutaneous oxygen monitor (TCOM). In the subject study, the ratsbreathed air and then were switched to breathing 100% oxygen at a timeequal to zero. Also at time zero, the rats were injected (intravenouslyin the femoral vein) with either saline (control), trehalose, glycinebetaine, or TSC.

FIGS. 2, 3, and 4 show that trehalose, TSC, or glycine betaine result inan increased oxygen transport across the skin. All of these compoundsincrease the TCOM readings, as shown in FIGS. 2, 3, and 4 by the averageincreases (±standard error). Thus, TSC, betaine and trehalose increaseoxygen transport in vivo.

It will be readily apparent to those skilled in the art that numerousmodifications and additions can be made to both the present compoundsand compositions, and the related methods without departing from theinvention disclosed.

1. A pharmaceutical composition comprising a diffusion enhancingcompound and a pharmaceutically acceptable carrier.
 2. A pharmaceuticalcomposition comprising a unit dose of a diffusion enhancing compound anda pharmaceutically acceptable carrier.
 3. A pharmaceutical compositionas in claim 1 wherein the diffusion enhancing compound is selected fromthe group consisting of trimethylamine N-oxide, proline, ectoine,trehalose and other disaccharides which increase hydrogen bonding,glycine betaine, 3-dimethylsulfoniopropionate, urea, maltose, glycerol,a small or multiply-charged ion with high charge density, t-butanol, andDMSO (dimethylsulfoxide).
 4. A pharmaceutical composition as in claim 1wherein the diffusion enhancing compound is selected from the groupconsisting of trehalose, glycine betaine, and proline.
 5. Apharmaceutical composition as in claim 3 wherein the small ormultiply-charged ion with high charge density is selected from the groupconsisting of SO₄ ²⁻, HPO₄ ²⁻, Mg²⁺, Ca²⁺, Li⁺, Na⁺, OH⁻, F⁻, and Cl⁻.6. A pharmaceutical composition as claim 1 wherein the composition is anaqueous based solution.
 7. A pharmaceutical composition as in claim 1wherein the pharmaceutically acceptable carrier is selected from thegroup consisting of cyclodextrins, PEG and glycols.
 8. (canceled)
 9. Amethod of treating hemorrhagic shock in a mammal comprisingadministering to said mammal a therapeutically effective amount of adiffusion enhancing compound other than a bipolar trans carotenoid. 10.A method of treating a hypoxic condition in a mammal comprisingadministering to said mammal a diffusion enhancing compound other than abipolar trans carotenoid in an amount sufficient to increase tissueoxygenation.
 11. A method of treating respiratory disease, asthma,emphysema, ALI, ARDS, COPD in a mammal comprising administering to saidmammal a therapeutically effective amount of a diffusion enhancingcompound other than a bipolar trans carotenoid.
 12. A method of treatingcardiovascular disease, myocardial infarction, hypertension, ischemia orstroke, in a mammal comprising administering to said mammal atherapeutically effective amount of a diffusion enhancing compound otherthan a bipolar trans carotenoid.
 13. A method of treating traumaticbrain injury or Alzheimer's disease in a mammal comprising administeringto said mammal a therapeutically effective amount of a diffusionenhancing compound other than a bipolar trans carotenoid.
 14. A methodof treating anemia in a mammal comprising administering to said mammal atherapeutically effective amount of a diffusion enhancing compound otherthan a bipolar trans carotenoid.
 15. A method of treating chronic renalfailure in a mammal comprising administering to said mammal atherapeutically effective amount of a diffusion enhancing compound otherthan a bipolar trans carotenoid.
 16. A method of treating cancer in amammal comprising administering before during or after radiation therapyor chemotherapy to said mammal a therapeutically effective amount of adiffusion enhancing compound other than a bipolar trans carotenoid. 17.A method of treating hypertension or myocardial infarction in a mammalcomprising administering to said mammal a therapeutically effectiveamount of a diffusion enhancing compound other than a bipolar transcarotenoid.
 18. A method of treating diabetes, diabetic retinopathy,peripheral vascular disease/claudication, or spinal stenosis/neurogenicclaudication in a mammal comprising administering to said mammal atherapeutically effective amount of a diffusion enhancing compound otherthan a bipolar trans carotenoid.
 19. A method as in claim 9, wherein thediffusion enhancing compound is selected from the group consisting oftrimethylamine N-oxide, proline, ectoine, maltose, trehalose and otherdisaccharides which cause increased hydrogen bonding, glycine betaine,3-dimethylsulfoniopropionate, urea, glycerol, a small ormultiply-charged ion with high charge density, t-butanol, and DMSO(dimethylsulfoxide).
 20. A method as in claim 9, wherein the diffusionenhancing compound is selected from the group consisting of trehalose,glycine betaine, and proline.
 21. A method as in claim 9, wherein saidadministration is selected from the group consisting of nasal,parenteral, transdermal, intramuscular injection and oral delivery. 22.A method of treating Wegener's granulomatosis in a mammal comprisingadministering to said mammal a therapeutically effective amount of adiffusion enhancing compound.
 23. A method of treating cancer in amammal comprising administering to said mammal a therapeuticallyeffective amount of a diffusion enhancing compound as an adjunct toradiation therapy and/or chemotherapy.
 24. A method of treatingarthritis in a mammal comprising administering to said mammal atherapeutically effective amount of a diffusion enhancing compound otherthan crocetin.
 25. A method as in claim 22, 23 or 24, wherein thediffusion enhancing compound is a bipolar trans carotenoid.
 26. A methodas in claim 22, 23 or 24, wherein the diffusion enhancing compound isTSC.